1.0 PROJECT SUMMARY The scientific premise of this application is that the individualized translational research process of the Undiagnosed Diseases Network (UDN) developed during Phase I is scalable and that its impact on patients, families, and disease discovery can be advanced and sustained by addition of a Clinical Site at Washington University School of Medicine (WUSM). WUSM represents a large academic medical center that is fully integrated with world-renowned basic science capabilities and demonstrated expertise in a gene first approach for patients with undiagnosed diseases. The highly collaborative clinical and biomedical research culture at WUSM promotes interactions within and across Departments, with institutional genomic, clinical, computational, and model system experts, and with colleagues regionally, nationally, and internationally. These interactions support recruitment, selection, evaluation, diagnosis discovery, and follow up of pediatric and adult patients with undiagnosed diseases through both established networks and individual referrals. Building on this infrastructure, WUSM faculty and staff will advance the success of the UDN in diagnosing and managing disease in undiagnosed patients by, first, using, refining, and improving protocols designed during Phase I of the UDN for comprehensive, timely clinical evaluations of 30 undiagnosed patients annually. Secondly, we will collect, securely store, and share standardized, high-quality clinical and laboratory data including genotyping, phenotyping, and documentation of environmental exposures and promote an integrated and collaborative community across the UDN and among laboratory and clinical investigators focused on defining the pathophysiology, cell biologic, and molecular mechanisms that cause these difficult to diagnose diseases. Thirdly, the WUSM UDN Clinical Site will propose a bioinformatics plan for leveraging institutional infrastructure and expertise to develop innovative strategies to improve discovery of pathogenic variants. Fourthly, the assessment, dissemination, outreach, and training plan will accelerate assessment and dissemination of data, protocols, consent materials, and methods, availability of educational and outreach materials for participants, clinicians, and other researchers, engagement of underrepresented minorities, and training for students, fellows, staff, and faculty in collaboration with WUSM?s Clinical and Translational Science Award infrastructure. Finally, WUSM will make a clear institutional commitment to maintain its Clinical Site, to adapt UDN Phase I practices for sustainability, to contribute to formation of a sustainable national UDN resource, and to adapt to unique needs and unexpected circumstances that may arise once Common Fund support ends in fiscal year 2022.